Scott A. Fuller

Mapping of semantic, phonological, and orthographic verbal working memory in normal adults with functional magnetic resonance imaging

Twelve neurologically normal participants (4 men and 8 women) performed semantic, phonological, and orthographic working memory tasks and a control task during functional magnetic resonance imaging. Divergent regions of the posterior left hemisphere used for decoding and storage of information emerged in each working memory versus control task comparison. These regions were consistent with previous literature on processing mechanisms for semantic, phonological, and orthographic information. Further, working memory versus control task differences extended into the left frontal lobe, including premotor cortex, and even into subcortical structures. Findings were consistent with R. C. Martin and C. Romanis (1994) contention that different forms of verbal working memory exist and further suggest that a reconceptualization of premotor cortex functions is needed.

Physiological and behavioural effects of the endogenous cannabinoid, arachidonylethanolamide (anandamide), in the rat.

1 Arachidonylethanolamide (AEA; anandamide) has been isolated from mammalian brain and found to bind to, and is thought to be, an endogenous ligand for the cannabinoid receptor. In order to understand better its behavioural and physiological properties, we have examined its acute effects in unanaesthetized freely behaving rats. 2 Intravenous AEA caused dose‐related decreases in locomotor behaviour, a pronounced hyperreflexia, and a moderate antinociceptive state. At doses between 3 and 30 mg kg−1, a dose‐dependent hypothermia and profound, time‐dependent cardiovascular changes were also observed. 3 An immediate bradycardia exceeding 50% was seen within 10–15 s of administration and lasted up to 11 min following the highest dose of the drug. In contrast, the change in mean arterial pressure was biphasic: an immediate 20% decrease in mean arterial pressure followed by a significant increase in blood pressure that lasted about 13 min after the highest dose. 4 These data demonstrate that AEA in the unanaesthetized rat exerts behavioural and physiological effects generally similar to those seen following natural cannabinoids and synthetic cannabimimetic agents and suggests a role for AEA in regulation of various physiological processes.

Determination of Drug-Induced Changes in Functional MRI Signal Using a Pharmacokinetic Model

As the applications of functional magnetic resonance imaging (fMRI) expand, there is a need for the development of new strategies for data extraction and analysis that do not require the presentation of stimuli in a repeated on/off pattern. A description and evaluation of a method and computer algorithm for the detection and analysis of brain activation patterns following acute drug administration using fMRI are presented. A waveform analysis protocol (WAP) input function has been developed that is based upon the single‐dose pharmacokinetics of a drug of interest. As a result of this analysis, regional brain activation can be characterized by its localization and intensity of activation, onset of action, time to peak effect, and duration of action. A global statistical test for significant drug effects based upon the probability of a voxel being activated by a saline vehicle injection is applied to grouped data on a voxel by voxel basis. Representative data are presented using nicotine as a prototypical agent. Using this method, statistically significant drug‐induced brain activation has been identified in several key cortical and subcortical brain regions. Hum Brain Mapping 8:235–244, 1999.

Cocaine's time action profile on regional cerebral blood flow in the rat

Cocaine is a powerful psychostimulant the high abuse liability of which in man appears to be linked, at least in part, to its pharmacokinetic properties. For example, intravenous and inhalation routes of administration result in appreciably higher level of dependence than either the oral or intranasal route, while cocaines behavioral and physiologic profile is both route- and time-dependent. Therefore, to determine if various aspects of the drugs profile of effects are due to alterations in regional neuronal activity, we measured the effects of cocaine on regional cerebral blood flow (rCBF) 1, 2, 5, 15 and 45 min after a single 1.0 mg/kg i.v. cocaine injection. rCBF is known to directly reflect the state of local neuronal activity and, when measured autoradiographically using the method of Sakurada et al., can be resolved with a very high temporal resolution (30 s). A heterogeneous pattern of cerebral activation was seen. Of those regions which responded to cocaine, all but three did so with a threshold to effect of less than 1 min. Several groups of structures were evident: (1) those regions where blood flow returned to baseline prior to the 5 min measurement group (including several amygdaloid nuclei and lateral septum); (2) those returning to baseline prior to the 15 min sacrifice point (including limbic cortex); (3) regions activated for at least 15 but less than 45 min (including such motor-related regions as the caudate, substantia nigra and globus pallidus); and (4) those demonstrating persistent rCBF alterations for the entire 45 min observation period (including nucleus accumbens, olfactory tubercle, hippocampus, various thalamic nuclei and medial prefrontal cortex). It thus appears that cocaines duration of action varies heterogenously across both time and brain structure, with many limbic regions displaying either very brief or prolonged duration of action while many motor-related structures display intermediate times of action. This regionally distinct time-course may reflect the diverse behavioral profile seen after cocaine administration in the rat.

Cannabinoid-Induced Alterations in Regional Cerebral Blood Flow in the Rat

A specific receptor for cannabinoids has been characterized at the pharmacological, molecular, and neuroanatomical level. However, less is known of the functional localization in the brain for the behavioral and physiological actions of these drugs. We have examined the effects of delta 9-tetrahydrocannabinol (THC) and its active metabolite 11-OH-THC on regional cerebral blood flow in the rat in order to determine functional CNS sites of action for the cannabinoids. Conscious rats were injected i.v. with one of four doses of THC (0.5, 1, 4, 16 mg/kg). 11-OH-THC (4 mg/kg), or vehicle 30 min prior to sacrifice. Regional cerebral blood flow was determined autoradiographically using the freely diffusible tracer method of Sakaruda et al. Changes in regional cerebral blood flow were observed in 16 of the 37 areas measured. Decreases in regional cerebral blood flow following THC were seen in such areas as the CA1 region of the hippocampus, frontal and medial prefrontal cortex, the nucleus accumbens, and the claustrum. Thresholds for these effects ranged from 0.5 to 16 mg/kg. Areas unaffected by THC include the medial septum, ventral tegmental area, caudate, temporal, parietal and occipital cortex, and cerebellum. These data indicate that THC and its active metabolite, 11-OH-THC, cause a heterogeneous alteration in the activity of specific CNS sites, many of which are involved in the characteristic behavioral actions of THC.

Selective Effects of the Endogenous Cannabinoid Arachidonylethanolamide (Anandamide) on Regional Cerebral Blood Flow in the Rat

Recent biochemical data suggest that arachidonylethanolamide (AEA; anandamide) may be an endogenous ligand for brain cannabinoid receptors. The functional neuronal consequences of AEA binding to cannabinoid receptors are only poorly understood. Using regional cerebral blood flow (rCBF) as an indirect marker of neuronal activity, acute AEA administration dose-dependently depressed rCBF in unanesthetized rats. Although 3.0 mg/kg was ineffective in altering rCBF, 10 mg/kg led to a decrease in rCBF in seven brain areas including the amygdala, cingulate, frontal, prepyriform, sensorimotor, and claustrocortex. An additional 16 areas responded in a similar manner to AEA, but only after 30 mg/kg, including the CA1 and CA3 regions of the hippocampus, the rostral core portion of the nucleus accumbens, and rostral caudate nucleus. Most of these rCBF effects dissipated between 15 and 20 min after drug administration, with only 4 regions, the basomedial and lateral amygdala, CA3 hippocampus and claustrocortex still depressed 60 min after an acute drug injection. No significant changes in heart rate, blood pressure, or blood gases were seen at the time of rCBF measurement, suggesting that the observed drug effects were neuronally mediated. Taken together with existing behavioral data, these data support the hypothesis that an endogenous cannabinoid neural system exists in mammalian brain and may help to explain the unique behavioral profile seen after cannabinoid administration.

Effects of heroin and naloxone on cerebral blood flow in the conscious rat

The widespread, heterogeneous distribution of opiate receptors and their endogenous ligands in the nervous system are reflective of the variety of central and systemic effects seen after opiate administration. Most neurons respond to either systemic or local opiate application with a decrease in firing rate, although increased neuronal activity has also been reported in such regions as the caudate, amygdala, ventral tegmentum, and substantia nigra. While regional metabolic studies have consistently reported neuronal suppression, some portion of this might be secondary to systemic hypercapnia. Using a brief blood flow marker, we recently reported a heterogenous increase in activity in more than half of the brain regions examined. To extend that study, we report herein the results of a dose-response and antagonist challenge experiment. Rats received an acute injection of one of the following: heroin (0.1, 0.3 or 1.0 mg/kg), naloxone (1.0 mg/kg), a cocktail of heroin (0.3 mg/kg) plus naloxone or saline. One min after drug administration, 160 muCi/kg [1-14C] octanoate, a marker for cerebral blood flow, was delivered IV. Rats were sacrificed two min later, brains removed and prepared for autoradiography. Of the fifty-eight areas analyzed, heroin caused an increase in blood flow in the caudate, claustrocortex, laterodorsal thalamus and dentate gyrus. Decreases were found for the bed nucleus of the stria terminalis, preoptic area, basolateral nucleus of the amygdala, dorsomedial and paraventricular hypothalamus, entorhinal and cingulate cortices and dorsal raphe. Naloxone resulted in significant increases in the olfactory tubercle and paraventricular nucleus while decreases were seen in the cingulate and basolateral amygdala.